GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized "tramlining" on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.

The Impact of Hospital Surgical Volume on Healthcare Utilization Outcomes After Pediatric Thyroidectomy.

BACKGROUND: A positive relationship between an individual surgeon's operative volume and clinical outcomes after pediatric and adult thyroidectomy is well-established. The impact of a hospital's pediatric operative volume on surgical outcomes and healthcare utilization, however, are infrequently reported. We investigated associations between hospital volume and healthcare utilization outcomes following pediatric thyroidectomy in Canada's largest province, Ontario. METHODS: Retrospective analysis of administrative and health-related population-level data from 1993 to 2017. A cohort of 1908 pediatric (<18 years) index thyroidectomies was established. Hospital volume was defined per-case as thyroidectomies performed in the preceding year. Healthcare utilization outcomes: length of stay (LOS), same day surgery (SDS), readmission, and emergency department (ED) visits were measured. Multivariate analysis adjusted for patient-level, disease and hospital-level co-variates. RESULTS: Hospitals with the lowest volume of pediatric thyroidectomies, accounted for 30% of thyroidectomies province-wide and performed 0-1 thyroidectomies/year. The highest-volume hospitals performed 19-60 cases/year. LOS was 0.64 days longer in the highest, versus the lowest quartile. SDS was 83% less likely at the highest, versus the lowest quartile. Hospital volume was not associated with rate of readmission or ED visits. Increased ED visits were, however, associated with male sex, increased material deprivation, and rurality. CONCLUSIONS: Increased hospital pediatric surgical volume was associated with increased LOS and lower likelihood of SDS. This may reflect patient complexity at such centers. In this cohort, low-volume hospitals were not associated with poorer healthcare utilization outcomes. Further study of groups disproportionately accessing the ED post-operatively may help direct resources to these populations.

Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study.

CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Pamidronate as first-line treatment of hypercalcemia in neonatal subcutaneous fat necrosis: A case series.

BACKGROUND: Subcutaneous fat necrosis (SCFN) can be complicated by severe hypercalcemia, which is frequently asymptomatic. Nephrocalcinosis is associated with hypercalcemia and, in other clinical settings, has been linked to furosemide and glucocorticoid use. First-line bisphosphonate therapy treating hypercalcemia in neonatal SCFN is not well described. OBJECTIVES: To describe the biochemical changes and risk of nephrocalcinosis in infants with hypercalcemia, secondary to neonatal SCFN, treated with initial pamidronate. METHODS: A retrospective chart review of five infants treated with initial pamidronate and without furosemide or glucocorticoids. Data were collected on the following: timing of presentation, therapeutic response, and presence of nephrocalcinosis. RESULTS: Hypercalcemia resolved after 2.8±1.7 days; this is compared to 7.6±2.8 days from previously reported cases utilising alternative therapies (P=0.012). There were no episodes of rebound hypercalcemia or hypocalcemia. Nephrocalcinosis was present in four of five cases. When including published cases, age at diagnosis was associated with presenting serum calcium (P=0.003) and nephrocalcinosis was associated with higher serum calcium (P=0.014) and time from SCFN to hypercalcemia diagnosis (P=0.002). CONCLUSIONS: This retrospective case series demonstrates that first-line pamidronate treatment was effective and safe in the resolution of hypercalcemia. Nephrocalcinosis was observed, despite the avoidance of furosemide and glucocorticoid therapy, and associated with greater disease severity and duration of hypercalcemia.

Lung Metastasis in Children with Differentiated Thyroid Cancer: Factors Associated with Diagnosis and Outcomes of Therapy.

Background: Lung metastasis from differentiated thyroid cancer (DTC) in children and young adults (CAYA) is estimated at 25%, which is 3-4 times higher than in adults. Lung metastases may respond to radioactive iodine (RAI) therapy and overall survival is excellent. Associations with lung metastasis include lateral lymph node (LN) disease although CAYA data are limited. We investigated factors associated with lung metastasis in children and adolescents and described their presentation and outcome. Methods: A retrospective review of medical records from 1998 to 2017 in patients aged <18 years treated at a tertiary pediatric center was carried out. Data on age, clinical features at diagnosis, histology, biochemistry, imaging, RAI therapy, and outcome were collected. Results: Patients treated for DTC totaled 98 and 19 of 98 (19%) patients had lung metastasis; 17 of 19 (89%) patients were identified within 6 months from thyroidectomy. Patients with lung metastasis were younger (p < 0.001)-40% <13 years old had lung metastasis-and had a larger primary tumor diameter (p = 0.01). Absence of LN disease had negative predictive values ≥90% (p < 0.02). Patients with lung metastasis had a higher postoperative thyrotropin-stimulated thyroglobulin (Tg) (p < 0.001), ≥2 ng/mL in 10 of 11 (91%) patients, and 100% had an elevated preoperative Tg (>60 ng/mL). Post-therapy whole body scan (WBS) identified most metastasis (13 of 17 patients), which were mostly diffuse (11 of 19 patients). Discordant findings were found between WBS and computed tomography (CT) at diagnosis (2 patients), WBS and CT during surveillance (3 patients), and diagnostic and post-therapy WBS (2 patients). Final outcome was "excellent" in 3 of 19 (16%) patients, "biochemically persistent" in 1 of 19 (5%) patients, "structurally persistent" in 13 of 19 (68%) patients-including 1 death-and indeterminate in 2 of 19 (11%) patients. Postoperative Tg correlated with response to therapy. Lung metastasis pattern and RAI cumulative activity were not predictive of response to therapy. Conclusions: Lung metastases are mostly observed at diagnosis of DTC and higher suspicion should be maintained in CAYA who are younger, have LN disease, and have elevated postoperative Tg. Preoperative Tg shows promise as another predictive marker, but limited sample size precludes generalization. "Excellent" response to therapy is uncommon-multiple RAI courses do not necessarily improve outcome-response appears unrelated to RAI activity or metastasis pattern.

Screening for Nonclassic Congenital Adrenal Hyperplasia in the Era of Liquid Chromatography-Tandem Mass Spectrometry.

CONTEXT: Screening for and diagnosing non classic congenital adrenal hyperplasia (NCCAH) uses serum 17-hydroxyprogesterone (17OHP) thresholds established from immunoassay data; however, a new liquid-chromatography tandem mass spectrometry (LC-MS/MS) method results in lower 17OHP values. The evolution of immunoassays is also challenging our diagnostic cut-off for glucocorticoid insufficiency and few data re-evaluate the utility of testing for glucocorticoid insufficiency in NCCAH. OBJECTIVE: (1) Evaluate the 17OHP threshold that predicts NCCAH in children using LC-MS/MS, and (2) determine the prevalence of glucocorticoid insufficiency in NCCAH. METHODS: A retrospective chart review of pediatric patients who underwent ACTH stimulation tests with cortisol and 17OHP measurements from 2011 to 2018 for assessment of NCCAH. Other adrenal pathologies were excluded. A cortisol < 415 nmol/L defined glucocorticoid insufficiency. Published correlation data determined a 17OHP of 3.3 nmol/L by LC-MS/MS was equivalent to 6 nmol/L by immunoassay. Data analysis was by measures of diagnostic accuracy. RESULTS: Of 188 patients included, 23 (12%) had NCCAH (21/23 had genetic confirmation); the remaining 2 had peak 17OHP > 30 nmol/L. Baseline 17OHP ≥ 6 nmol/L most accurately screened for NCCAH-sensitivity and specificity 96%. Almost all genetically confirmed NCCAH (20/21) had peak 17OHP > 30 nmol/L; all subjects with other diagnoses peaked < 30 nmol/L. Glucocorticoid insufficiency was present in 55% with NCCAH. CONCLUSIONS: Despite the increased specificity of LC-MS/MS, a baseline 17OHP ≥ 6 nmol/L most accurately screened for NCCAH; this supports current practice guidelines. This threshold identified all with glucocorticoid insufficiency, notably prevalent in our cohort and for whom glucocorticoid stress dosing should be considered.

Evaluation of growth hormone stimulation testing in children.

OBJECTIVE: To evaluate the use and interpretation of growth hormone (GH) stimulation tests used across the UK for diagnosing GH deficiency. BACKGROUND: Previous studies show poor consensus on the use of GH stimulation tests. Sex steroid priming and retesting in the transition period are areas not previously surveyed. DESIGN: Data were collected from tertiary paediatric endocrinologists, paediatricians with a specialist interest in endocrinology and biochemists across the UK over 6 months through distributing electronic surveys. RESULTS: At least three different GH stimulation tests were used by 33% of departments. Glucagon and insulin doses varied most, and sampling frequency varied most using insulin. All laboratories use a recommended chemiluminescence immunoassay with an acceptable coefficient of variability. The GH peak for diagnosing GH deficiency varied from 6 to 8 µg/l. A wide range of clinical scenarios prompted retesting in the transition period, suggesting nonstandardized current practice. Seventy-five per cent of departments use sex steroid priming, but follow criteria variously combining bone age, chronological age and pubertal stage, together with variations in steroid type and dose. CONCLUSIONS: Although a contentious diagnostic test, GH stimulation tests remain the gold standard for diagnosing GH deficiency. Our data suggest that together with variation in indication, protocol and interpretation, there is considerable variation in current practices pertaining to priming and retesting in transition. Given the current financial climate and the need for careful resource management, this study emphasizes the considerable need for consensus in the investigation, diagnosis and long-term follow-up of these children, at least nationally if not internationally.

Characterization of management and outcomes of patients with acromegaly in Vancouver over 30 years.

PURPOSE: The purpose of this study was to characterize the management and outcomes of patients with acromegaly seen in single center in Vancouver, British Columbia, Canada over a 30 year period. METHODS: The study involved retrospective data collection from charts of patients diagnosed with acromegaly since 1980: 130 patients (63 male and 67 female) were included in the analysis, with a mean age at diagnosis of 43 years (male) and 47 years (female). RESULTS: The most common presenting features included acral enlargement, coarse facial features, sweating/oily skin and headache. All cases were caused by pituitary adenomas, of which 58.5% were macroadenomas and of these, 30.8% were invasive. The most common co-morbidities were hypertension 31.5%, arthralgia 28%, diabetes 27.7% and sleep apnea 23.8%. The vast majority (88.5%) of patients was treated surgically and of these patients, 21.5% also received radiotherapy and 66.9% received medical therapy. When stringent cure criteria were applied (based on latest growth hormone (GH) and IGF-1 results) the outcomes were 35.4% cured or controlled, 30% remained active, 15.4 discordant results and 19.2 % with no results reported. Twenty eight percent of patients who underwent surgery and 32% of patients who underwent radiotherapy were not cured but symptoms were moderately well controlled with medical therapy. CONCLUSION: Based on the size of population studied, this study showed a prevalence of acromegaly of 29 per million. The cure rate was low following surgery but with adjuvant medical treatment disease control was achieved in most individuals.